Photoreactive compounds and compositions

ABSTRACT

The present invention provides a compound of formula (I): Pt IV (N 3 ) 2 X 1 X 2 Y 1 Y 2 , wherein X 1  and X 2  are the same or different and each one is a group NR 1 R 2 R 3  wherein R 1 , R 2  and R 3  are the same or different and each can be any one of H and optionally substituted alkyl, aryl, aralkyl, acyl, cycloalkyl, heterocyclyl, alkenyl, aralkenyl, alkinyl, cycloalkenyl, or X 1  and X 2  together represent a group R 1 R 2 NR 4 NR 1 R 2  wherein R 1  and R 2  have the same meaning as before, and R 4  represents an optionally substituted divalent, saturated or unsaturated, alkyl chain, an optionally substituted divalent, saturated or unsaturated cycloalkyl or an optionally substituted divalent aryl, or R 4  or two or more of R 1 , R 2 , R 3  and R 4  and the respective N atom(s) to which they are linked, represent an optionally substituted heterocyclyl having at least one ring containing said N atom(s); and Y 1  and Y 2  are the same or different or when cis together represent a divalent moiety Y 3 , wherein at least one of Y 1  and Y 2 , or Y 3 , is a substantially labile ligand in the analogous Pt(II) complex without the azide groups, whilst being substantially resistant, in vivo, to hydrolysis and physiological reducing agents. One or more of R 1 , R 2 , R 3  and R 4 , may further represent a covalently bonded link to at least one further complex of formula (I) to form a dimer or oligomer, or to a targeting moiety having affinity for a predetermined tissue or cell type.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation-in-part of U.S. patent application Ser. No.10/487,758 for “Photoreactive Compounds and Compositions” filed on Feb.24, 2004, which issued as U.S. Pat. No. 7,176,327 on Feb. 13, 2007,which is a 371 of PCT/GB02/03939 filed Aug. 27, 2002, which claimspriority of GB 0120618.4 filed Aug. 24, 2001.

FIELD OF THE INVENTION

The present invention relates to novel photoreactive compounds andcompositions, their preparation and their use in the preparation ofchemotherapeutic agents as anticancer drugs.

BACKGROUND OF THE INVENTION

Cisplatin (cis-[PtCl₂(NH₃)₂]) is one of the most widely used platinum(Pt) based therapeutic anticancer drugs. Such Pt (II) compounds do,however, exhibit severe side effects due to their indiscriminate anduncontrollable cytotoxic effects which include nausea, neurotoxicity andrenal toxicity. The drug is believed to exert its cytotoxicity throughbinding DNA, particularly to adjacent GG bases. Additional disadvantagesof Pt (II) based drugs are associated with their intravenousadministration route, which requires increased medical attention andoften results in additional complications and discomfort for the patientthan would be the case if oral administration was possible. Anotherproblem frequently associated with the use of cisplatin is the acquiredresistance of tumour cells to the drug following an initial treatment.

Such disadvantages have prompted the search for alternative and improvedanticancer drugs and therapies. Presently clinical trials are underwayusing oral administration of Pt (IV) compounds such as theJohnson-Matthey compound JM216. Pt (IV) compounds are substantiallyinert to substitution and can act as a good precursor for highlyreactive Pt (I) compounds, which readily undergo substitution. Ideally,such conversion of Pt (IV) to Pt (II) would occur at the target side ofthe tumour in a controlled manner. The presently available Pt (IV)compounds are, however, thought to be reduced to active Pt (II) speciesin the blood and, hence, are also accompanied by the adverse sideeffects of indiscriminate cytotoxicity associated with cisplatin. Bloodplasma is particularly rich in powerful reducing agents such asglutathione (GSH), cysteine, and ascorbate, whereby, once administeredto the body, Pt (IV) compounds are vulnerable to reduction andactivation.

Another anti-cancer strategy which has been used, namely photodynamictherapy, entails irradiation with visible or near-infrared light togenerate, highly reactive and cytotoxic, singlet oxygen species viaporphyrin mediated conversion of triplet oxygen. Advances in lasers andfibre optics have enabled more or less highly localised delivery of thelight to tumours of epithelial origin. Such targeted cytotoxicity ishighly desirable in the treatment of tumours and there is a need for acompound which is substantially stable both ex vivo, and in vivo afteradministration, but is activatable to a cytotoxic form in a spatiallyand temporally controlled manner whilst being substantially non-toxicand physiologically acceptable prior to activation, and it is an objectof the present invention to provide such a compound.

SUMMARY OF THE INVENTION

The present invention overcomes many of the disadvantages of existingPt-based anti-cancer drugs by providing novel, water soluble,biologically inert Pt (IV) compounds which can be converted to acytotoxic Pt (II) species by photoactivation.

In a first aspect, the present invention provides novel compounds whichare Pt (IV) complexes of the general formula I:Pt(N₃)₂X¹X²Y¹Y²  (I)wherein X¹ and X² are the same or different and each one represents agroup of the general formula NR¹R²R³ wherein R¹, R² and R³ are the sameor different and in each case each one may represent any one of H andoptionally substituted alkyl, aryl, aralkyl, acyl, cycloalkyl,heterocyclyl, alkenyl, aralkenyl, alkinyl, cycloalkenyl, or X¹ and X²together represent a group of the general formula R¹R²NR⁴NR¹R² whereinR¹ and R² have the same meaning as hereinbefore, and R⁴ represents anoptionally substituted divalent, saturated or unsaturated, alkyl chainpreferably having 2 or 3 carbon atoms between the N atoms, an optionallysubstituted divalent, saturated or unsaturated cycloalkyl or anoptionally substituted divalent aryl, or R⁴ or two or more of R¹, R², R³and R⁴ and the respective N atom(s) to which they are linked, representan optionally substituted heterocyclyl having at least one ringcontaining said N atom(s); and Y¹ and Y² are the same or different or,when in a cis position, as a further alternative they may togetherrepresent a divalent moiety Y³, wherein at least one of Y¹ and Y², orY³, is a substantially labile ligand in the analogous Pt (II) complexcorresponding to general formula (I) without the azide groups, whilstbeing substantially resistant, in vivo, to hydrolysis and physiologicalreducing agents, and one or more of R¹, R², R³ and R⁴, may represent acovalently bonded link to at least one further complex of formula I soas to form a dimer or oligomer, or to a targeting moiety having affinityfor a predetermined tissue or cell type; and wherein X¹ and X² arepreferably in a cis configuration.

Where any of the groups in general formula I have been indicated asbeing optionally substituted then each of the substituents could beselected from hydroxyl, alkoxyl, aralkoxyl, carboxy, halogen,trihaloalkyl, and carbonyl.

Where two or more of R¹, R², R³ and R⁴ and the respective N atomrepresent heterocyclyl, typical examples of NR¹R²R³ include pyridyl,quinolyl, isoquinolyl and picolyl, whilst typical examples ofR¹R²NR⁴NR¹R² include bipyridyl, phenanthrolyl, 1,2-diaminophenyl and1,2-diaminocyclohexyl.

For the avoidance of doubt, unless otherwise indicated to the contrary,the following terms have the indicated meanings:

“Alkyl” includes unsubstituted and substituted, straight and branched,chain groups, which are generally C1 to C10, preferably C1 to C6 (i.e.have 1 to 10, preferably 1 to 6 carbon atoms in the alkyl chain).

“Cycloalkyl” includes unsubstituted and substituted cycloalkyl groups,which are generally C3 to C5, preferably C3 to C6.

“Alkenyl” includes unsubstituted and substituted, straight and branched,chain groups, which are generally C1 to C10, preferably C1 to C6, andhave at least one double bond in the chain.

“Cycloalkenyl” includes unsubstituted and substituted cycloalkyl groupswhich are generally C4 to C5, preferably C4 to C6, and have at least onedouble bond in the ring.

“Alkynyl” includes unsubstituted and substituted, straight and branched,chain groups, which are generally C1 to C10, preferably C1 to C6, andhave at least one triple bond in the chain.

“Aryl” includes unsubstituted and substituted aromatic groups having atleast one aromatic ring, usually a C6 ring.

“Heterocyclyl” includes unsubstituted and substituted cyclic groupshaving at least one ring which generally has from 3 to 7 atoms in thering, of which at least one is a heteroatom selected from N, O and S.Typical examples having at least one N atom include pyridine, pyrrole,pyrimidine, pyridazine, pyrazole and imidazole. Typical examples havingat least one O atom include furan and glucose. A typical example havingat least one S atom is thiophene. Typical examples having at least twodifferent hetero atoms include oxazole and thiazole.

“Aralkyl” includes alkyl groups as defined hereinbefore which have anaryl substituent, for example, benzyl or phenethyl, and may beunsubstituted or substituted.

“Alkoxyl” (or alkoxy) has the same meaning as alkyl when bonded tooxygen, for example, methoxy.

“Aryloxyl” (or aryloxy) and “Aralkyl” (or alkaryloxy) have the samemeaning as aryl and aralkyl when bonded to oxygen, for example phenoxyor benzyloxy.

It will be appreciated that in order to reduce the dosage required ofthe compounds of the present invention, these may, as indicated above,incorporate a targeting moiety having affinity for a predeterminedtissue or cell type. Suitable moieties include, for example,aminophosphonate ligands which tend to bind to bone and thus haveparticular utility in the use of compounds of formula I for thetreatment of bone cancers, or a receptor-specific ligand such as, forexample, serotonin. It is also possible to utilise Pt (IV) complexes ofthe present invention which are bound to suitable polymeric ordendrimeric materials in generally known manner, in order to facilitatedelivery thereof to a desired site in the body.

As noted herein before two or more complexes of general formula I may belined together so as to form a dimer or oligomer. Various kinds of linkmay be used. One convenient form of link in the case of an R¹ and/or R²group is an alkyl chain, generally an at least C4, preferably a C4 to C5chain.

Suitably labile Y¹ and Y² ligands generally comprise halogen, especiallychlorine, or more preferably, an OY⁴ group wherein Y⁴ represents H or aY⁵CO group wherein Y⁵ represents R, RNH, or RCS, wherein R represents anoptionally substituted C1 to C12 alkyl. Suitably labile Y³ ligandsinclude groups of the general formula OOC(CY⁶R⁷)_(n)CY⁸Y⁹O wherein eachof Y⁶ and Y⁷ can represent H or a substituent or Y⁶ and Y⁷ togetherrepresent cycloalkyl, and n is 0, 1 or 2 and each of Y⁸ and Y⁹ canrepresent H or a substituent, or together represent oxygen. Preferredexamples of Y³ include oxalate and 1,1-dicarboxycyclobutane (CBDCA).

Advantageously one or more of the R¹, R², R³, R⁴, Y¹, Y² and Y³ groupsis chosen so as to promote solubility in polar solvents, especiallywater or to enhance lipophilicity, in order to facilitate delivery ofthe complexes of formula I to a desired site in the body. Lipophilicitymay be enhanced by the presence of aromatic groups or hydrocarbon chainshaving an extended chain length. Water solubility may be enhanced by thepresence of polar groups such as carboxylate groups (for example thosepresent in any of the Y¹, Y² and Y³ groups), and/or salt forming groups.In the latter case salts are desirably formed with physiologicallyacceptable counterions.

Particularly preferred compounds of formula I which may be mentionedinclude:

-   Cis,trans,cis-[Pt^(IV)(N₃)₂(OH)₂(NH₃)₂];-   Cis,trans-[Pt^(IV)(en)(N₃)₂(OH)₂] (where en represents    ethylenediamine);-   Trans,cis,cis-[Pt^(IV)(OCOCH₃)₂(N₃)₂(NH₃)₂];-   [Pt^(IV)(NH₃)₂(CBDCA)trans-(N₃)₂] (where CBDCA represents    1,1-dicarboxycyclobutane);-   Cis,trans-[cis-dach(N₃)₂(OH)₂] (where dach represents    diaminocyclohexane)

In a modified form of the invention only one of Y¹ and Y² is a labileligand and the other could represent any other convenient group which isresistant to hydrolysis and physiological reducing agents or couldrepresent a further N₃ group or a X³ group wherein X³ may be the same asor different to X¹ and X² and has the same general formula as X¹ and X².

Compounds of formula I have been found to have good stability in aqueoussolution, as well as in blood plasma, saline solution and glutathione(GSH) aqueous solution, with individual compounds having been found tobe stable in aqueous solution for 2 months or more (when kept in thedark) with little or no azide ligands being replaced or substituted. Aparticular advantage of the present invention is the substantialstability of the compounds of formula I in blood plasma. Previouslyknown orally active Pt (IV) based drugs are reduced to Pt (II) in bloodplasma. Compounds of the present invention have been found to remaininert and stable under physiological conditions, including blood plasmaand GSH solution, overcoming existing problems associated with oraladministration of less stable Pt (IV) compounds. Resistance to reductionby glutathione (GSH) is particularly advantageous as this“physiological” reducing agent is particularly powerful and prevalentunder normal physiological conditions.

The relative inertness of the compounds of the present invention may,though, be readily overcome by photoactivation, with the Pt (IV) azidecompounds of the present invention being converted to active Pt (II)compounds which may include compounds of formula II:PtX¹X²Y¹Y²  (II)upon photoactivation.

Photoactivation may be effected by use of radiation of suitablewavelength. In general there may be used radiation having a wavelengthof from 350 to 800 nm, preferably from 450 to 500 nm, most preferablyabout 458 nm which has been found to be particularly efficient atphotoactivating the compounds of the present invention. Radiation oflonger wavelength within the preferred range can be used, for example,red light which has better penetration through body tissue, though lowerenergy and photoactivation of the compounds of the present invention hasbeen achieved using red light oft for example, 647 nm wavelength. It ispossible to increase the effectiveness of the longer wavelengthradiation, such as red light, by employing techniques such as frequencydoubling lasers so as to deliver to the target site radiation with thedesired increased energy levels over that of longer wavelength redlight, for photo reduction of the Pt (IV) complexes to Pt (II)complexes.

By controlling and targeting the photoactivating radiation, theconversion of the relatively inert Pt (IV) compounds of formula I intoactive Pt (II) compounds may be effected in a more or less preciselyspatially and temporally controlled manner.

The compounds of the present invention and their products followingphotoactivation have been analysed by a number of techniques including1D ¹H and 2D [¹H,¹⁵N] heteronuclear-single-quantum coherence (HSQC) NMRspectroscopy, 2D [¹H,¹⁵N] HSQC-total correlation spectroscopy(HSQC-TOCSY) NMR spectrometry, electrospray mass spectrometry, and X-raycrystallography, which has confirmed their structure and identifiedtheir reaction products under various conditions. These techniques havealso been used to show that following photoactivation of the Pt (IV)complexes to Pt (II) complexes, the photoactivated products bind to GMP(guanosine monophosphate), GG dinucleotide and polynucleotides showingthem to be suitable for use as cytotoxic agents for use in cancertherapy, whose cytotoxicity may be targeted and controlled.

With regard to products obtained following irradiation of the compoundsof formula I, NMR spectroscopy data which has been obtained indicatesthat in at least some cases, a number of different more or less stablePt (II) complex species is obtained from a given Pt (IV) compound offormula I. In a further aspect the present invention provides as newproducts and/or intermediate reactive species, especially for use incancer therapy, any such compounds or intermediate reactive specieswhich are novel.

The skilled addressee will appreciate that compounds of formula I may beobtained in different cis- and trans-form configurations of the azide,X¹ and X², and Y¹ and Y² groups, and it should be understood that all ofthese are encompassed within the scope of the present invention. Whereone of Y¹ and Y² is also an azide or X¹/X² group, so that there arethree identical groups, it will be appreciated that these could bepresent in different isomeric forms viz mer, where the three identicalgroups are all cis to each other, or fac, where the three groups arecoplanar.

The compounds of the present invention can be prepared by any suitablemethod known in the art for compounds of similar structure. For examplea compound of the formula Pt^(II)(N₃)₂X¹X² may be oxidized to a compoundof the formula Pt^(II)(N₃)₂X¹X²Q¹Q² wherein Q¹ and Q² may be the same asY¹ and Y² as defined hereinbefore or different, and where Q¹ and/or Q²is a group(s) other than Y¹ or Y² respectively, or together represent agroup other than Y³, replacing any such Q¹, Q² or Q³ group with said Y¹,Y² or Y³ group(s). In general compounds of general formula I wherein Y¹and Y² are both OH can be readily made by oxidation of the analogousPtII compound in which Y¹ and Y² are absent, with hydrogen peroxide soas to add the OH groups. Other compounds of general formula I can thenbe made by reacting the abovementioned OH-group containing compound witha suitable reactant so as to replace or condense with the OH group.Thus, for example, reaction with a carboxyalkyl anhydride would yieldthe corresponding carboxyalkyl substituted compound of general formulaI. Further details of suitable processes are described in theliterature, for example, in “Platinum and other Metal CoordinationCompounds in Cancer Chemotherapy”, Plenum Press, New York (1991) at pp.93-100.

The analogous PtII compounds referred to above are convenientlyobtainable by reaction of a compound of general formula III:PtX¹X²Z¹Z²  (III)wherein X¹ and X² have the same meaning as before and Z¹ and Z² areconveniently halogen, for example, I or Cl, with silver nitrate tofacilitate replacement of the halogen moiety with an azide moiety, ingenerally known manner.

Another route for obtaining compounds of general formula I is by meansof a substitution reaction with the analogous Pt(IV) compound of formulaIV:PtX¹X²Y¹Y²Z³Z⁴  (IV)wherein X¹, X², Y¹ and Y² have the same meaning as in formula I, and Z³and Z⁴ are the same or different and each is a suitably labile leavinggroup such as hydroxyl. The compound of formula IV may be reacted withexcess azide salt, conveniently sodium azide.

The compounds of the present invention can be used to treat variouskinds of tumours including non-malignant tumours and malignant tumoursincluding breast, ovarian, skin, mouth, throat, colon, gastrointestinaltract, and colorectal carcinomas, as well as leukaemias, myelomas,lymphomas and other such disorders of the blood and lymphatic system.

Thus in a further aspect the present invention provides a method oftreating a cancer in a patient comprising the steps of administering acompound which is a complex of formula I to the patient, andsubsequently irradiating said compound with light. In the case of atumour of a body tissue, the tumour itself will normally be irradiatedin situ. In the case of conditions such as leukaemias and other suchcirculatory disorders, there would generally be used a suitabletargeting moiety, for example a suitable antibody for binding thecomplex to the abnormal cells. In such cases it would generally beconvenient to carry out the irradiation step extra-corporeally, bypassing blood from the patient through an irradiation apparatus, andthen returning the treated blood to the patient.

In another aspect the present invention provides a method of treatmentof a tumour in a patient comprising the steps of administering acompound which is a complex of formula I to the patient, andsubsequently irradiating the tumour with light. It will be appreciatedthat the light radiation intensity and dose should be sufficient topenetrate the tumour and convert an effective amount, preferablysubstantially all, of the amount of the compound of formula I present inand/or on the tumour.

The present invention can in principle be used to treat any condition inwhich it is desired, selectively to kill off abnormal or cells presentin the body. Where the cells are not localized, then it would normallybe necessary to use a suitable targeting moiety to localize thecompounds of the invention in direct proximity to said cells uponadministration thereof.

Thus in yet another aspect the present invention provides a method oftreatment of a condition in a patient in which abnormal cells arepresent in the body, comprising the steps of; providing a compoundcomprising a complex of formula I as defined hereinbefore wherein one ormore of R¹, R², R³ and R⁴ represents a covalently bonded link to atargeting moiety having affinity for said abnormal cell; administeringsaid compound to the patient; and irradiating the compound.

As discussed above the compound may be irradiated directly in the bodyor extra-corporeally.

In another aspect the present invention provides a pharmaceuticalformulation comprising a compound of formula I as defined hereinbefore,or a pharmaceutically acceptable salt thereof, together with apharmaceutically acceptable carrier therefor.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Formulations according to the present invention include those suitablefor systemic administration as well as those suitable for directapplication to the tumour. More particularly they include oral, topical,rectal or parenteral (including intravenous) administration. Preferredformulations are those suitable for oral, or parenteral administration.

The formulations may conveniently be presented in unit dosage form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include step of bringing the active compound intoassociation with a carrier which constitutes one or more accessoryingredient. In general, the formulations are prepared by uniformly andintimately bringing the compound of the present invention intoassociation with a liquid carrier or a finely divided solid carrier orboth and then, if necessary, shaping the product into desiredformulations.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units as capsules, cachets, tablets orlozenges, each containing a predetermined amount of the active compound;as a powder or granules; or a solution or suspension in an aqueous ornon-aqueous liquid such as a syrup, an elixir, an emulsion or a draught.Other kinds of formulations such as teas or infusions, may also be used.

A tablet may be made by compression or moulding, optionally with one ormore accessory ingredient(s). Compressed tablets may be prepared bycompressing in a suitable machine the active compound in a free-flowingform, such as a powder or granules, optionally mixed with a binder,lubricant, inert diluent, surface active or dispersing agent. Mouldedtablets may be made by moulding in a suitable matching a mixture of thepowdered active compound with any suitable carrier.

A syrup may be made adding the active compound to a concentrated,aqueous solution of a sugar, for example sucrose, to which may also beadded any accessory ingredients. Such accessory ingredient(s) mayinclude flavorings, an agent to retard crystallization of the sugar oran agent to increase the solubility of any other ingredients, such as apolyhydric alcohol for example glycerol or sorbitol.

Formulations for rectal administration may be presented as a suppositorywith a conventional carrier such as cocoa butter.

Formulations suitable for parenteral administration convenientlycomprise a sterile aqueous preparation of the active compound which ispreferably isotonic with the blood of the recipient. Such formulationssuitably comprise a solution of a compound of Formula (I) that isisotonic with the blood of the recipient.

Useful formulations also comprise concentrated solutions or solidscontaining a compound of the present invention which upon dilution withan appropriate solvent give a solution for parenteral administration asabove.

In addition to the aforementioned ingredients, formulations of thisinvention may further include one or more accessory ingredient(s)selected from diluents, buffers, flavouring agents, binders,surfactants, thickeners, lubricants, preservatives (includingantioxidants) and the like.

Further preferred features and advantages of the invention will appearfrom the following examples provided for the purposes of illustration.

Experimental Procedures

In Examples 1 and 2, ¹⁵N (greater than 98% abundance of the ¹⁵N isotope)NH₄Cl (obtained from Aldrich of Gillingham, UK) and ethylenediamine (en)(prepared by ourselves from N¹⁵ phthalimide using the method describedin E. Zang & P. J. Sadler in Synthesis 1997 pp 410-412), were used inorder to facilitate the use of NMR spectroscopy for the purposes ofinvestigating the properties of the novel compounds obtained. It will ofcourse be understood that normally there would be used natural abundance¹⁵N materials, and the preparative procedures using the latter materialswould be substantially identical to those described in Examples 1 and 2.Example 3 describes such an equivalent procedure for Example 1, andExample 4 describes an alternative procedure for Example 2 using naturalabundance ¹⁵N materials, though enriched ¹⁵N materials could likewise beused.

NMR spectroscopy was carried out using procedures as described in detailin S. J. Berners-Price & P. J. Sadler, Coordination Chemistry Reviews151 (1996) at pp 19-26, by 1D ¹H and 2D [¹H,¹⁵N]heteronuclear-single-quantum coherence (HSQC) NMR spectroscopy and inthe case of cis,trans-[Pt^(IV)(en)(N₃)₂(OH)₂] also 2D [¹H,¹⁵N]HSQC-total correlation spectroscopy (HSQC-TOCSY) NMR spectroscopy.

EXAMPLE 1 Preparation of Cis,trans,cis-[Pt^(IV)(N₃)₂(OH)₂(NH₃)₂]

K₂[PtCl₄] (1 g, 2.41 mmol) was dissolved in 50 ml deionized water in a100 ml round-bottomed flask. 10 molar equivalents (mol eq.) of KI wereadded and the solution stirred for 30 min. at room temperature. 2 moleq. of ¹⁵NH₄CL (0.26 g, 4.88 mmol) was added to the solution. The pH wasadjusted with 1 M NaOH to 11. The yellow precipitate was filtered andwashed with water, ethanol and ether. The yellow solid(cis-[Pt(¹⁵NH₃)₂I₂]) was dried in a desiccator over silica gel.cis-[Pt(¹⁵NH₃)₂I₂] (0.2 g, 0.43 mmol) and 2 mol eq. AgNO₃ (0.146 g, 0.86mmol) was added in a round-bottomed flask. 20 ml deionized water wasadded and the suspension was stirred in the dark for 24 hours. TheAgI-precipitate was twice filtered off with an inorganic membrane filter(Whatman, Anotop 10, 0.02 μm). 20 mol eq. of NaN₃ (0.57 g, 8.77 mmol)was added and the solution stirred for 30 min. in the dark at roomtemperature. The solvent volume was reduced to 10 ml and the flask putin the fridge overnight. The yellow precipitate was washed with etherand dried in air. Yield: 97 mg (72%). 10 ml of deionized water was addedto cis-[Pt(N₃)₂(NH₃)₂] (0.086 g, 0.27 mmol). 40 eq. of H₂O₂ (1.2 ml 30%H₂O₂, 11.75 mmol) was added and the solution stirred in the dark at roomtemperature for 24 hours. The volume of the solution was reduced and theflask put in the fridge (4° C.) for 2 days. The yellow precipitate ofcis,trans,cis-[Pt^(IV)(N₃)₂(OH)₂(NH₃)₂] was filtered and washed withwater and ether. Yield: 32.8 mg (35%).

EXAMPLE 2 Preparation of Cis,trans-[Pt^(IV)(en)(N₃)₂(OH)₂]

¹⁵N-en.2HCl (0.052 g, 0.39 mmol) was dissolved in 10 ml deionized waterand the pH adjusted to 8 with 1 M NaOH. K₂ [PtCl₄] (0.162 g, 0.39 mmol)was added and the solution stirred at room temperature. The pH wasregularly adjusted to 8-9. The obtained yellow precipitate([Pt(¹⁵N-en)Cl₂]) was washed with water and ether and dried over P₂O₅.[Pt(¹⁵N-en)Cl₂] (0.04 g, 0.12 mmol) and 2 mol eq. AgNO₃ (0.041 g, 0.24mmol) were stirred in deionized water in the dark at room temperaturefor 24 hours in a round-bottomed flask. The white precipitate (AgCl) wastwice filtered off with an inorganic membrane filter (Whatman, Anotop10, 0 02 μm). 25 mol eq. NaN₃ (0.208 g, 3.2 mmol) was added to thesolution. The volume of the solution was reduced and the flask put inthe fridge for 2 days. The yellow precipitate was filtered and washedwith water and ether. Yield: 23.5 mg (57%). 5 ml deionized water wasadded to [Pt(en)(N₃)₂] (0.021 g, 0.06 mmol) in a 25 ml round-bottomedflask. 50 mol eq. of H₂O₂ (0.3 ml 30% H₂O₂, 2.9 mmol) was added to thesolution which was then stirred in the dark at room temperature for 24hours. The yellow precipitate of cis,trans-[Pt^(IV)(en)(N₃)₂(OH)₂] wasfiltered and washed with water and ether. Yield: 10 mg (40%).

EXAMPLE 3 Preparation of Cis,trans,cis-Pt^(IV)(N₃)₂(OH)₂(NH₃)₂]

KI (5.61 g, 33.79 mmol) was added to an aqueous solution of K₂[PtCl₄](1.40 g, 3.38 mmol, 50 ml). After stirring for 30 min at ambienttemperature, NH₄Cl (0.362 g, 6.76 mmol) was added and the pH adjusted to11 with 1 M NaOH. A yellow precipitate (cis-[Pt(NH₃)₂I₂]) appeared whichwas filtered off and washed with water, ethanol and ether and driedunder vacuum to yield 1.41 g (87%). AgNO₃ (2 mol equiv, 0.32 g, 1.89mmol) was added to a suspension of cis-[Pt(NH₃)₂I₂] (0.455 g, 0.94 mmol)in water (20 ml) which was then stirred in the dark for 24 h. TheAgI-precipitate was filtered off with an inorganic membrane filter(Whatman, Anotop 10, 0.02 pm). NaN₃ (20 mol equiv, 1.23 g, 18.86 mmol)was added and the solution stirred for 30 min in the dark at ambienttemperature. The solvent volume was reduced to 10 ml and the flask wasstored at 4° C. overnight. A yellow precipitate of cis-[Pt(N₃)₂(NH₃)₂]was obtained and washed with ether and dried in air to yield 212 mg(72%).

H₂O₂ (40 mol eq., 1.2 ml 30% H₂O₂, 11.75 mmol) was added to a suspensionof cis-[Pt(N₃)₂(NH₃)₂] (0.086 g, 0.27 mmol) in water (10 ml) which wasstirred in the dark at ambient temperature for 24 h. The volume of thesolution was reduced and on cooling to 4° C.,cis,trans,cis-[PtIV(N₃)₂(OH)₂(NH₃)₂] formed as a yellow precipitatewhich was filtered and washed with water and ether to yield 32.8 mg(35%). Crystals suitable for x-ray crystal structure determination weregrown from a water/ethanol (1/1 v/v) mixture at 4° C.

EXAMPLE 4 Preparation of Cis,trans-[Pt^(IV)(en)(N₃)₂(OH)₂]

K₂[PtCl₄] (1.48 g, 3.57 mmol) was added to an aqueous solution of KI (30ml, 5.51 g, 33.19 mmol) and the solution stirred at ambient temperature.Ethylenediamine (238 μl, 3.57 mmol) was added to the dark brownsolution. The yellow precipitate ([Pt^(II)(en)I₂]) was washed with waterand ether and dried under vacuum to yield 1.67 g (92%). [Pt^(II)(en)I₂](0.68 g, 1.34 mmol) and 2 mol eq. AgNO₃ (0.453 g, 2.67 mmol) werestirred in water in the dark at room temperature for 24 hours. The AgIprecipitate was filtered off and 25 mol eq. NaN₃ (1.74 g, 26.72 mmol)was added to the solution. The volume was reduced and a yellowprecipitate was obtained on cooling of the solution to 277 K. This waswashed with water and ether to yield 0.247 mg (55%) of[Pt^(II)(en)(N₃)₂]. H₂O₂ (25 mol eq., 1.5 ml 30% H₂O₂, 14.5 mmol) wasadded to a suspension of [Pt(en)^(II)(N₃)₂] (0.187 g, 0.55 mmol) inwater (15 ml). This was then stirred in the dark at ambient temperaturefor 24 h. The yellow precipitate of cis,trans-[Pt^(IV)(en)(N₃)₂(OH)₂]was filtered and washed with water and ether to yield 79 mg (38%).Crystals suitable for x-ray crystal structure determination wereobtained from an aqueous solution at 4° C.

EXAMPLE 5 Preparation of Trans,cis,cis-Pt^(IV)(OCOCH₃)₂(N₃)₂(NH₃)₂]

Deionized water (5 ml) was added to cis-[Pt^(IV)(N₃)₂(NH₃)₂] (0.028 g,0.09 mmol). H₂O₂ (0.5 ml 30% H₂O₂, 4.9 mmol) was added and the solutionstirred overnight at room temperature in the dark. The solvent was thenremoved on a rotary evaporator and the yellow precipitate driedovernight under vacuum. 5 ml dichloromethane was added to the yellowprecipitate. 4 ml of acetic anhydride (42.4 mmol) was dropwise addedunder cooling with an ice bath. The suspension was stirred for one weekin the dark. The pale yellow precipitate oftrans,cis,cis-[Pt^(IV)(OCOCH₃)₂(N₃)₂(NH₃)₂] was filtered with a paperfilter and washed with cold water and ether and then dried over silicagel. Yield: 25 mg (64%). Crystals suitable for x-ray crystal structuredetermination were obtained from an aqueous solution at 4° C.

EXAMPLE 6 Preparation of Cis,trans-[Pt^(IV)(cis-dach)(N₃)₂(OH)₂](dach=diaminocyclohexane)

cis-Diaminocyclohexane (120 μl, 1 mmol) was added to an aqueous solutionof K₂[[PtCl₄] (0.45 g, 1.08 mmol, 30 ml) and stirred for 30 min atambient temperature. The yellow precipitate ([Pt^(II)(cis-dach)Cl₂)])was filtered and washed with water and ether to yield 165.6 mg (40%).AgNO₃ (0.144 g, 0.85 mmol) was added to a suspension in water of[Pt^(II)(cis-dach)Cl²)] (0.165 g, 0.44 mmol, 20 ml) and stirredovernight at 333 K in the dark. The white AgCl precipitate was filteredoff with an inorganic membrane filter (Whatman, Anotop 10, 0.02 pm).NaN₃ (0.56 g, 8.61 mmol) was added which led to a colour change toyellow. The solution was stirred for 2 h at ambient temperature in thedark before filtering off the yellow precipitate of[Pt^(II)(cis-dach)N₃)₂] which was washed with water and ether. Crystalssuitable for X-ray diffraction were grown in water at 4° C. H₂O₂ (25 molequiv, 0.5 ml 30% H₂O₂, 4.9 mmol) was added to a suspension of[Pt^(II)(cis-dach)(N₃)₂] (0.067 g, 0.17 mmol) in water. The suspensionwas put in an ultrasonic bath for 10 min and then stirred overnight inthe dark at ambient temperature.

EXAMPLE 7 Stability of Cis,trans,cis-[Pt^(IV)(N₃)₂(OH)₂(NH₃)₂]

The stability of the compound under various conditions was examined bycomparing NMR spectra obtained at the beginning and end of theexperimental periods.

a) The compound obtained from example 1 (2 mg) was dissolved in bloodplasma (0.5 mls). No sign of any reduction product was detected after 2weeks.

b) An aqueous solution of the compound obtained from Example 1 (5 mM)was prepared. No sign of any hydrolysis was detected after 2 months.

c) A 5 mM solution of the compound obtained from example 1 was made upin 0.1M aqueous NaCl. The solution was examined after 2 days by means ofNMR spectroscopy. No evidence of any azide ligand substitution in thecompound from example 1 by chloride was found.

d) A 2 mM solution of the compound obtained from example 1 was made upin 5 mM aqueous glutathione. The solution was examined after having beenkept in the dark for 8 weeks by means of NMR spectroscopy. No evidenceof any reduction of the compound from example 1 by glutathione wasfound.

EXAMPLE 8 Photoactivation of Cis,trans,cis-[Pt^(IV)(N₃)₂(OH)₂(NH₃)₂]with blue light

An aqueous solution of the compound obtained from example 1 as describedin example 7b hereinabove, was irradiated with a low power energy lightsource at 20 mW with a wavelength of 457.9 nm, for 60 minutes. Thesolution was then examined by means of NMR spectroscopy which confirmedthe presence of species containing the cis-[Pt^(II)(NH₃)₂] moiety.

In more detail irradiation was carried out using an argon-krypton ionlaser (Coherent Innova 70C Spectrum) equipped with a fibre optic(FT-600-UMT, Ø (diameter) 600 μm; Elliot Scientific Ltd.) to deliverlight (λ=457.9 nm, 488 nm, 647.1 nm) directly into the sample within themagnet of the NMR spectrometer. The laser output, after the fibre, wasin the range of 10 to 75 mW, as measured by a Coherent 210 power meter.1D ¹H and 2D [¹H,¹⁵N] HSQC spectra were recorded on a Bruker DMX 500 NMRspectrometer (¹H 500.13 MHz, ¹⁵N 50.7 MHz) at a pH value of 5 usingsodium 3-(trimethylsilyl)propionate-2,2,3,3-d₄ (TSP, 0 ppm) as internalδ (¹H) standard. When cis,trans-[Pt^(IV)(en)(N₃)₂(OH)₂] was analysed ina similar way 2D [¹H,¹⁵N] HSQC-TOCSY spectra were also recorded. All δ(¹⁵N) were referenced externally to ¹⁵NH₄ ⁺ at δ=0. pH values weremeasured with a pH-meter (Orion 710A) equipped with a microcombinationelectrode (Aldrich) calibrated with Aldrich standard buffers (pH 4, 7and 10) and was adjusted with dilute solutions of HClO₄ and NaOH. Nocorrection was made for ²H isotope effects on the glass electrode.

EXAMPLE 9 Photoactivation of Cis,trans,cis-[Pt^(IV)(N₃)₂(OH)₂(NH₃)₂]with blue light and Binding to Dinucleotide

The procedure of example 8 was repeated with a solution containing 1 mMGG dinucleotide [d(GpG)]. Examination of the solution after irradiationusing NMR spectroscopy and electroscope mass spectrometry showed bindingof species containing the cis-[Pt^(II)(NH₃)₂] moiety to GG had takenplace.

EXAMPLE 10 Photoactivation of cis,trans-[Pt^(IV)(en)(N₃)₂(OH)₂] with redlight and Binding to Dinucleotide

A low power energy light source (75 mW) with a wavelength of 647.1 nmwas used to irradiate an aqueous 1 mM solution of the compound obtainedfrom example 4 containing 1 mM GG dinucleotide [d(GpG)] for 18.5 hrs.The solution was examined by means of NMR spectroscopy which confirmedbinding to the GC dinucleotide.

EXAMPLE 11 Binding to 14mer Polynucleotide

The procedure of example 9 was repeated with a 1 mM solution of apolynucleotide having the sequence ATACATGGTACATA, and using thecompound obtained in example 2 in place of that obtained in example 1.Examination of the solution after photoactivation thereof using NMRspectroscopy showed binding of species containing the cis-[PtII(en)]moiety to the GG moiety had taken place.

FURTHER EXAMPLES Trans,trans,trans-[Pt(N₃)₂(OH)₂(NH₃)₂] (FM137)

Trans-[PtCl₂(NH₃)₂] (0.102 g, 0.341 mmol) was suspended in H₂O and AgNO₃(0.664 mmol, 0.113 g) was added. The suspension was stirred in the darkat 333 K for 48 h, and then the AgCl precipitate was removed byfiltration with an inorganic membrane filter (Whatman, Anotop 10, 0.02μm). NaN₃ (1.32 mmol, 0.086 g) was added and the solution stirred in thedark for 24 h. Trans-[Pt(NH₃)₂(NH₃)₂] was collected by filtration andresuspended in H₂O (100 mL). Addition of H₂O₂ (30%, 2.64 mmol) followedby stirring for a further 6 h resulted in a cloudy yellow solution. Theinsoluble AgN₃ was filtered off and the solution concentrated. Crystalsappeared after storing at 277 K for 24 h. The bright yellow crystalswere filtered off, washed with water, ethanol and diethyl ether anddried under vacuum. Crystals suitable for X-ray analysis were grown fromH₂O at 277 K.

Trans,trans,trans-[Pt(N₃)₂(OH)₂(¹⁵NH₃)₂] was prepared fromtrans-[PtCl₂(¹⁵NH₃)₂].

Yield: 66.4 mg (56.2%)

¹H NMR (90% H₂O/10% D₂O, pH 4.75): δ 5.32 ppm (d, ¹⁵NH₃, ¹J(¹⁵N—¹H) 72.0Hz, 6H).

2D [¹H,¹⁵N] HSQC NMR: δ (¹H,¹⁵N/5.32, −41.65), ¹J(¹⁹⁵Pt—¹⁵N) 282 Hz,²J(¹⁹⁵Pt—¹H) 47.5 Hz.

¹⁹⁵Pt NMR (90% H₂O/10% D₂O): 875 ppm

ESI-MS; [M+Na]³⁰ 370.1 m/z

UV-vis: λ_(max)=286 nm (ε=18,945 M⁻¹cm⁻¹).

Trans,trans,trans-[Pt(N₃)₂(OH)₂(NH)₃)(py)] (FM165)Trans-[PtCl₂(NH₃)(Py)]

Cisplatin (0.106 g, 0.352 mmol) was suspended in H₂O (3 mL) and pyridine(py) added (1.056 mmol, 84.6 μL). After stirring at 348 K for 90 min,the clear solution was cooled to room temperature and reduced to drynessto give a white solid. HCl (2 M, 2 mL) was added and the solutionstirred at 343 K for 4 days. After cooling on ice, the yellow solid wasfiltered off, washed with water, ethanol and diethyl ether and driedunder vacuum.

Trans-[PtCl₂(¹⁵NH₃)(Py)] was prepared from cis-[PtCl₂(¹⁵NH₃)₂].

Yield: 0.100 g (78.7%)

¹H NMR (d₆-acetone): δ 8.85 (d, H_(o), ¹J_(o,m) 6.8 Hz, 2H), 7.98 (t,H_(p), ¹J_(p,m) 7.6 Hz, 1H), 7.45 (dd, H_(m), 2H), 3.86 (d, ¹⁵NH₃,¹J(¹⁵N—¹H) 72.0 Hz, 3H). 2D [¹H,¹⁵N] HSQC NMR: δ (¹H,¹⁵N/3.86, −70.28),¹J(¹⁹⁵Pt—¹⁵N) 276.7 Hz, ²J(¹⁹⁵Pt—¹H) 52.0 Hz.

b) Trans-[Pt(N₃)₂(NH₃)(py)]

Trans-PtCl₂(NH₃)(Py)] (97.4 mg, 0.269 mmol) was suspended in H₂O (25 mL)and AgNO₃ (1.98 mol eq, 89.1 mg) added. After stirring at 333 K for 24 hin the dark AgCl was removed by filtration with an inorganic membranefilter (Whatman, Anotop 10, 0.02 μm). NaN₃ (0.538 mmol, 35.0 mg) wasadded and the suspension stirred for 6 h in the dark. The volume wasreduced to 2 mL and left at 277 K for 24 h. The yellow precipitate wasfiltered off, washed with water, ethanol and diethyl ether and driedunder vacuum.

Yield: 92.9 mg (92.1%)

¹H NMR (d₆-acetone): δ 8.77 (d, H_(o), ¹J_(o,m) 6.8 Hz, 2H), 8.08 (t,H_(p), ¹J_(p,m) 7.5 Hz, 1H), 7.59 (dd, H_(m), 2H), 3.97 (d, ¹⁵NH₃,¹J(¹⁵N—¹H) 72.0 Hz, 3H). 2D [¹H,¹⁵N] HSQC NMR: δ (¹H,¹⁵N/3.97, −67.39),¹J(¹⁹⁵Pt—¹⁵N) 322.4 Hz, ²J(¹⁹⁵Pt—¹H) 53.5 Hz.

c) Trans,trans,trans-[Pt(N₃)₂(OH)₂(NH₃)(py)]

Trans-[Pt(N₃)₂(NH₃)(Py)] (92.0 mg, 0.245 mmol) was suspended in H₂O (300mL) and H₂O₂ (30%, 1.470 mmol 0.150 mL) added. After stirring overnightat room temperature in the dark, the volume was reduced to 20 mL and theremaining insoluble AgN₃ was removed by filtration. All the solvent wasremoved and acetone was added to precipitate the product, which wascollect by filtration and washed sparingly with ice cold water, ethanoland diethyl ether, then dried under vacuum. Crystals suitable for X-rayanalysis were grown from H₂O at 277 K.

Yield: 75.8 mg (74.8%)

¹H NMR (90% H₂O/10% D₂O, pH 5.12): δ 8.72 (d, H_(o), ¹J_(o,m) 6.0 Hz,2H), 8.25 (t, H_(p), ¹J_(p,m) 7.6 Hz, 1H), 7.78 (dd, H_(m), 2H), 5.65(d, ¹⁵NH₃, ¹J(¹⁵N—¹H) 74.0 Hz, 3H)

2D [¹H,¹⁵N] HSQC NMR: δ (¹H,¹⁵N/5.65, −46.00), ¹J(¹⁹⁵Pt—¹⁵N) 282.3 Hz,²J(¹⁹⁵Pt—¹H) 49.5 Hz.

ESI-MS: [M+Na]³⁰ 432.0 m/z

UV-vis: λ_(max)=289 nm (δ=18,816 M⁻¹cm⁻¹), 268 nm (ε=10,800 M⁻¹cm⁻¹).

Trans,trans,trans-[Pt(N₃)₂(OH)₂(NH₃)(MeNH₂)] (FM169)Trans-[PtCl₂(NH₃)(MeNH₂)]

Cisplatin (0.105 g, 0.351 mmol) was suspended in H₂O (2 mL) andmethylamine (MeNH₂, 40% solution, 1.404 mmol, 0.121 mL) added. Themixture was stirred under nitrogen at 343 K for 2 h or until thesolution was colourless. The volume was reduced to dryness and then HCl(1.7 M, 2.5 mL) was added. The reaction was stirred under nitrogen at348 K for 24 h then cooled on ice and filtered. The filtrate was placedback under nitrogen and heated at 373 K for 6 h, then 348 K for 12 h,cooled on ice and filtered again, this was repeated once more and allthree batches of solid were combined and washed with water, ethanol anddiethyl ether then dried under vacuum.

Yield: 77.5 mg (70.3%)

¹H NMR (d₆-acetone): δ 3.97 (s, NH₂, 2H), 3.37 (s, NH₃, 3H), 2.43 (t,CH₃, ¹J(CH₃—NH₂) 6.5 Hz, 3H).

b) Trans-[Pt(N₃)₂(NH₃)(MeNH₂)]

Trans-[PtCl₂(NH₃)(MeNH₂)] (75.9 mg, 0.242 mmol) was suspended in H₂O (25mL) and AgNO₃ (1.95 mol eq, 80.1 mg) added. The reaction was stirred inthe dark at 333 K for 24 h then filtered with an inorganic membranefilter (Whatman, Anotop 10, 0.02 μm). NaN₃ (0.968 mmol, 63.0 mg) wasadded and the yellow solution was stirred for 4 h, then reduced todryness. Small amounts of H₂O were added and the product filtered,washed with ethanol and diethyl ether then dried under vacuum. Crystalssuitable for X-ray analysis were grown from H₂O at 277 K.

Yield: 61.3 mg (77.6%)

¹H NMR (d₆-acetone): δ 4.20 (s, NH₂, 2H), 3.70 (s, NH₃, 3H), 2.45 (t,CH₃, ¹J(CH₃—NH₂) 6.5 Hz, 3H).

c) Trans,trans,trans-[Pt(N₃)₂(OH)₂(NH₃)(MeNH₂)]

Trans-[Pt(N₃)₂(NH₃)(MeNH₂)] (59.8 mg, 0.183 mmol) was suspended in H₂O(20 mL) and H₂O₂ (0.732 mmol, 0.083 mL) added. After stirring in thedark at room temperature for 1 h the solvent was removed. Ethanol wasadded to precipitate the product which was filtered, washed sparinglywith ice cold water, ethanol and diethyl ether then dried under vacuum.

Yield: 53.7 mg (81.3%)

¹H NMR (90% H₂O/10% D₂O): δ 2.36 (septet, CH₃, 3H).

ESI-MS: [M+H]⁺ 362.1 m/z

UV-vis: λ_(max)=286 nm (ε=19,384 M⁻¹cm⁻¹).

Trans,trans,trans-[Pt(N₃)₂(OH)₂(NH₃)(EtNH₂)] (FM170)Trans-[PtCl₂(NH₃)(EtNH₂)]

Cisplatin (94.6 mg, 0.315 mmol) was suspended in H₂O (1.5 mL) andethylamine (EtNH₂, 70% solution, 2.520 mmol, 0.121 mL) added. Thereaction was heated at 363 K for 2 h or until the solution wascolourless, and then the solvent removed. The white solid wasredissolved in HCl (2.5 M, 1.5 mL). The solution was stirred at 363 Kfor 48 h, cooled to room temperature and placed on ice for 2 h. Thebright yellow solid was filtered, washed with water, ethanol and diethylether and dried under vacuum.

Yield: 76.6 mg (74.1%)

¹H NMR (d₆-acetone): δ 3.98 (s, ¹⁴NH₂, 2H), 3.38 (d, ¹⁵NH₃, ¹J(¹⁵N—¹H)72.0 Hz, 3H), 2.75 (sextet, CH₂, 2H), 1.27 (t, CH₃, ¹J(CH₂—CH₃) 7.0 Hz,3H).

2D [¹H,¹⁵N] HSQC NMR: δ (¹H,¹⁵N/3.38, −68.38), ¹J(¹⁹⁵Pt—¹⁵N) 258.7 Hz,²J(¹⁹⁵Pt—¹H) 51.0 Hz.

Trans-[Pt(N₃)₂(NH₃)(EtNH₂)]

Trans-[PtCl₂(NH₃)(EtNH₂)] (40.6 mg, 0.124 mmol) was suspended in H₂O (20mL) and AgNO₃ (1.95 mol eq, 41.1 mg) added. The reaction was stirred inthe dark at 333 K for 24 h then filtered with an inorganic membranefilter (Whatman, Anotop 10, 0.02 μm). NaN₃ (0.744 mmol, 48.3 mg) wasadded and the yellow solution was stirred for 24 h, then reduced todryness. Small amounts of H₂O were added and the product filtered,washed with ethanol and diethyl ether and dried under vacuum.

Yield: 33.9 mg (80.3%)

¹H NMR (d₆-acetone): δ 4.20 (s, ¹⁴NH₂, 2H), 3.70 (d, ¹⁵NH₃, ¹J(¹⁵N—¹H)60.0 Hz, 3H), 2.77 (sextet, CH₂, 2H), 1.32 (t, CH₃, ¹J(CH₂—CH₃) 6.0 Hz,3H).

2D [¹H,¹⁵N] HSQC NMR: δ (¹H,¹⁵N/3.70, −43.59), ¹J(¹⁹⁵Pt—¹⁵N) 247.4 Hz,²J(¹⁹⁵Pt—¹H) 41.5 Hz.

Trans,trans,trans-[Pt(N₃)₂(OH)₂(NH₃)(EtNH₂)]

Trans-[Pt(N₃)₂(NH₃)(EtNH₂)] (33.5 mg, 0.098 mmol) was suspended in H₂O(30 mL) and H₂O₂ (0.392 mmol, 0.041 mL) added. After stirring in thedark at room temperature for 1 h the solution was filtered. All thesolvent was removed and then ethanol added to precipitate the product.The yellow solid was collected by filtration, washed sparingly with icecold water, ethanol and diethyl ether and dried under vacuum.

Yield: 26.7 mg (72.7%)

ESI-MS: [M+H]⁺ 375.9 m/z

UV-vis: λ_(max)=285 nm (16,516 M⁻¹cm⁻¹)

¹H NMR (90% H₂O/10% D₂O, pH 4.87): 5.71 (s, NH₂, 2H), 5.29 (d, ¹⁵NH₃,¹J(¹⁵N—¹H) 73.3 Hz, 3H), 2.89 (sextet, CH₂, 2H), 1.33 (t, CH₃,¹J(CH₂—CH₃) 7.3 Hz, 3H).

2D [¹H,¹⁵N] HSQC NMR: δ (¹H,¹⁵N/5.29, −41.35), ¹J(¹⁹⁵Pt—¹⁵N) 265.2 Hz,²J(¹⁹⁵Pt—¹H) 46.7 Hz.

Trans,trans,trans-[Pt(N₃)₂(OH)₂(NH₃)(2-pic)] (FM171)Trans-[PtCl₂(NH₃)(2-pic)]

Cisplatin (0.103 g, 0.343 mmol) was suspended in H₂O (1 mL) and2-picoline (1.372 mmol, 0.1277 g) added. The reaction was stirred at 348K for 2.5 h and then refluxed for 30 min. The solvent was removed andHCl (2.7 M, 1.5 mL) added. The solution was stirred at 378 K for 5 hthen cooled to 277 K for 24 h and filtered. The filtrate was returned toheat at 378 K for a further 6 h and then cooled to 277 K and filteredagain. The two batches of yellow solid were combined and washed withwater, ethanol and diethyl ether and dried under vacuum.

Trans-[PtCl₂(¹⁵NH₃)(2-picoline)] was synthesized from ¹⁵N-cisplatin.

Yield: 88.3 mg (68.5%)

¹H NMR (d₆-acetone): δ 8.80 (d, H-6, ¹J 5.7 Hz, 1H), 7.78 (td, H-4, ¹J7.7 Hz, ²J 1.5 Hz, 1H), 7.43 (d, H-3, ¹J 7.7 Hz, 1H), 7.27 (t, H-5, 1H),3.68 (s, NH₃, ¹J(¹⁵N—¹H) 72.0 Hz, 1H), 3.13(s, CH₃, 3H).

2D [¹H,¹⁵N] HSQC NMR: δ (¹H,¹⁵N/3.68, −69.67), ¹J(¹⁹⁵Pt—¹⁵N) 267.0 Hz,²J(¹⁹⁵Pt—¹H) 53.0 Hz.

Trans-[Pt(N₃)₂(NH₃)(2-pic)]

Trans-[PtCl₂(NH₃)(2-pic)] (87.3 mg, 0.232 mmol) was suspended in H₂O (50mL) and DMF (0.5 mL). AgNO₃ (1.95 mol eq, 76.9 mg) was added and thereaction stirred in the dark at 333 K for 24 h. All the solvent wasremoved and the solid redissolved in H₂O (50 mL). NaN₃ (0.928 mmol, 60.3mg) was added and the solution stirred for 4 h, the volume was thenreduced to 3 mL and the bright yellow solid filtered, washed with water,ethanol and diethyl ether and dried under vacuum.

Yield: 81.2 mg (90.0%)

¹H NMR (d₆-acetone): δ 8.95 (d, H-6, ¹J 5.9 Hz, 1H), 7.89 (td, H-4, ¹J7.7 Hz, ²J 1.7 Hz, 1H), 7.59 (d, H-3, 1H) 7.42 (t, H-5, 1H), 3.74 (s,NH₃, ¹J(¹⁵N—¹H) 72.0 Hz, 3H), 3.20(s, CH₃, 3H).

2D [¹H,¹⁵N] HSQC NMR: δ (¹H,¹⁵N/3.74, −65.78), ¹J(¹⁹⁵Pt—¹⁵N) 334.0 Hz,²J(¹⁹⁵Pt—¹H) 55.2 Hz.

Trans,trans,trans-[Pt(N₃)₂(OH)₂(NH₃)(2-pic)]

Trans-[Pt(N₃)₂(NH₃)(2-pic)] (80.0 mg, 0.206 mmol) was suspended in H₂O(500 mL) and H₂O₂ (30%, 0.824 mmol, 0.085 mL) added. The reaction wasstirred in the dark at room temperature for 24 h and then the volume wasreduced to 50 mL. The yellow solution was filtered to remove anyremaining AgN₃ and then reduced to dryness. Small amounts of H₂O wereadded and the solid recovered by filtration and washed with water,ethanol and diethyl ether then dried under vacuum. Crystals suitable forX-ray analysis were grown from H₂O at 277 K.

Yield: 64.9 mg (73.4%)

ESI-MS: [M+Na]⁺ 446.6 m/z

UV-vis: λ_(max)=292 nm (17,888 M⁻¹cm⁻¹), 276 nm (sh, 14,500 M⁻¹cm⁻¹)

¹H NMR (90% H₂O/10% D₂O, pH 5.04): δ 8.66 (d, H-6, ¹J 6.4 Hz, 1H), 8.04(td, H-4, ¹J 7.7 Hz, 1H), 7.54 (d, H-3, 1H) 7.51 (t, H-5, 1H), 5.67 (d,¹⁵NH₃, ¹J(¹⁵N—¹H) 74.2 Hz, 3H), 3.06 (d, CH₃, 3H).

2D [¹H,¹⁵N] HSQC NMR: δ (¹H,¹⁵N/5.67, −44.65), ¹J(¹⁹⁵Pt—¹⁵N) 300.6 Hz,²J(¹⁹⁵Pt—¹H) 50.4 Hz.

Trans,trans,trans-[Pt(N₃)₂(OH)₂(NH₃)(tz)] (FM172) Trans-[PtCl₂(NH₃)(tz)]

Cisplatin (81.8 mg, 0.273 mmol) was suspended in H₂O (2 mL) and thiazole(tz, 0.819 mmol, 0.058 mL) added. The reaction was stirred at 343 K for2 h, brought to reflux, then cooled. HCl (3.276 mmol, 0.273 mL) wasadded and the solution stirred at 378 K for 6 h. After cooling to roomtemperature the product was further precipitated by cooling on ice, thenfiltered, washed with water, ethanol and diethyl ether and dried undervacuum.

Yield: 77.7 mg (77.3%)

¹H NMR (d₆-acetone): δ 9.53 (dd, H-2, ²J_(2,4) 0.9 Hz, ²J_(2,5) 2.4 Hz,1H), 8.29 (dd, H-4, ¹J_(4,5) 3.7 Hz, 1H), 7.81 (dd, H-5, 1H), 3.81 (s,NH₃, 3H).

Trans-[Pt(N₃)₂(NH₃)(tz)]

Trans-[PtCl₂(NH₃)(tz)] (40.3 mg, 0.110 mmol) was suspended in H₂O (20mL) and AgNO₃ (1.98 mol eq, 36.9 mg) added. The reaction was stirred inthe dark at 333 K for 24 h, then filtered with an inorganic membranefilter (Whatman, Anotop 10, 0.02 μm). NaN₃ (0.440 mmol, 28.6 mg) wasadded and the solution stirred in the dark at room temperature for 24 h.The volume was reduced to 2 mL and the yellow product collected byfiltration, washed with water, ethanol and diethyl ether and dried undervacuum.

Yield: 32.3 mg (77.4%)

¹H NMR (d₆-acetone): δ 9.42 (dd, H-2, ²J_(2,4) 0.9 Hz, ²J_(2,5) 2.4 Hz,1H), 8.12 (dd, H-4, ¹J_(4,5) 3.7 Hz, 1H), 7.95 (dd, H-5, 1H), 4.07 (s,NH₃, 3H).

Trans,trans,trans-[Pt(N₃)₂(OH)₂(NH₃)(tz)]

Trans-[Pt(N₃)₂(NH₃)(tz)] (31.7 mg, 0.083 mmol) was suspended in H₂O (500mL) and H₇O₂ (30%, 0.332 mmol, 0.034 mL) added. After stirring in thedark at room temperature for 24 h, the volume was reduced to 15 mL andfiltered. All solvent was then removed and acetone added to precipitateproduct. The yellow solid was filtered off and washed sparingly withice-cold water, ethanol and diethyl ether, and dried under vacuum.

Yield: 24.8 mg (71.2%)

ESI-MS: [M+H]⁺ 415.9 m/z

UV-vis: λ_(max)=289 nm (15,234 M⁻¹cm⁻¹), 236 nm (8,630 M⁻¹cm⁻¹).

¹H NMR (90% H₂O/10% D₂O): δ 9.51 (dd, H-2, ²J_(2,4) 1.0 Hz, ²J_(2,5) 2.4Hz, 1H), 8.24 (dd, H-4, ¹J_(4,5) 3.6 Hz, 1H), 8.04 (dd, H-5, 1H).

Trans,trans,trans-[Pt(N₃)₂(OH)₂(NH₃)(4-pic)] (FM174)Trans-[PtCl₂(NH₃)(4-pic)]

Cisplatin (0.148 g, 0.494 mmol) was suspended in H₂O (4 mL) and4-picoline (1.483 mmol, 0.1381 g) added. The reaction was stirred at 378K for 1 h or until colourless, then HCl (5.93 mmol, 0.495 mL) added. Thesolution was stirred at 363 K for 12 h then cooled and placed on ice toprecipitate the product, which was collected by filtration. The filtratewas returned to heat at 363 K for a further 12 h and then cooled andfiltered again. The two batches of yellow solid were combined and washedwith water, ethanol and diethyl ether and dried under vacuum.

Yield: 0.126 g (67.9%)

¹H NMR (d₆-acetone): δ 8.66 (d, H-2, H-6, ¹J_((2,6-3,5)) 6.6 Hz, 2H),7.26 (d, H-3, H-5, 2H), 3.71 (s, NH₃, 3H), 2.41 (s, CH₃, 3H).

Trans-[Pt(N₃)₂(NH₃)(4-pic)]

Trans-[PtCl₂(NH₃)(4-pic)] (45.9 mg, 0.122 mmol) was suspended in H₂O (40mL) and DMF (200 μL). AgNO₃ (2 mol eq, 41.3 mg) was added and thereaction stirred in the dark at 333 K for 24 h. NaN₃ (1.22 mmol, 79.4mg) was added and the solution stirred for 24 h, then all the solventwas removed. H₂O (2 mL) was added and the yellow solid collected byfiltration and washed with water, ethanol and diethyl ether and driedunder vacuum.

Yield: 40.0 mg (84.2%)

¹H NMR (d₆-acetone): δ 8.57 (d, H-2, H-6, ¹J_((2,6-3,5)) 6.6 Hz, 2H),7.41 (d, H-3, H-5, 2H), 3.94 (s, NH₃, 3H), 2.46 (s, CH₃, 3H).

Trans,trans,trans-[Pt(N₃)₂(OH)₂(NH₃)(4-pic)]

Trans-[Pt(N₃)₂(NH₃)(4-pic)] (19.4 mg, 0.050 mmol) was suspended in H₂O(200 mL) and H₂O₂ (30%, 0.20 mmol, 0.020 mL) added. The reaction wasstirred in the dark at room temperature for 24 h and then the volume wasreduced to ˜20 mL. The yellow solution was filtered to remove anyremaining AgN₃ and then reduced to dryness. Small amounts of H₂O wereadded and the solid recovered by filtration and washed with water,ethanol and diethyl ether then dried under vacuum.

Yield: 14.4 mg (68.2%)

ESI-MS: [M+Na]³⁰ 424.0 m/z

UV-vis: λ_(max)=289 nm (14,318 M⁻¹cm⁻¹)

¹H NMR (90% H₂O/10% D₂O): δ 8.51 (d, H-2, H-6, ¹J_((2,6-3,5)) 6.8 Hz,2H), 7.60 (d, H-3, H-5, 2H), 2.58 (s, CH₃, 3H).

Trans,trans,trans-[Pt(N₃)₂(OH)₂(NH₃)(2-bromo-3-methylpyridine)] (FM181)Trans-[PtCl₂(NH₃)(2-Br-3-Me-pyridine)]

Cisplatin (132.8 mg, 0.443 mmol) was suspended in H₂O (4 mL) and2-bromo-3-methylpyridine (1.328 mmol, 0.1479 mL) added. The reaction wasstirred at 378 K for 1 h or until colourless, then HCl (5.31 mmol, 0.443mL) added. The solution was stirred at 368 K for 24 h then cooled andplaced on ice to precipitate the product, which was collected byfiltration. The filtrate was returned to heat at 368 K for a further 24h and then cooled and filtered again. The two batches of yellow solidwere combined and washed with water, ethanol and diethyl ether and driedunder vacuum.

Yield: 84.1 mg (41.8%)

¹H NMR (d₆-acetone): δ 8.69 (d, H-6, ¹J_(5,6) 5.9 Hz, 1H), 7.85 (d, H-4,¹J_(4,5) 7.5 Hz, 1H), 7.41 (d, H-5, 1H), 3.79 (s, NH₃, 31, 2.46 (s, CH₃,3H).

Trans-[Pt(N₃)₂(NH₃)(2-Br-3-Me-pyridine)]

Trans-[PtCl₂(NH₃)(2-Br-3-Me-pyridine)] (37.5 mg, 0.0824 mmol) wassuspended in H₂O (15 mL) and DMF (200 μL). AgNO₃ (1.99 mol eq, 27.9 mg)was added and the reaction stirred in the dark at 333 K for 24 h. NaN₃(0.824 mmol, 53.6 mg) was added and the solution stirred for 24 h, thenall the solvent was removed. H₂O (2 mL) was added and the yellow solidcollected by filtration and washed with water, ethanol and diethyl etherand dried under vacuum.

Yield: 25.2 mg (65.3%)

¹H NMR (d₆-acetone): δ 8.83 (d, H-6, ¹J_(5,6) 5.7 Hz, 1H), 7.96 (d, H-4,¹J_(4,5) 7.5 Hz, 1H), 7.56 (d, H-5, 1H), 3.67 (s, NH₃, 3H), 2.46 (s,CH₃, 3H).

Trans,trans,trans-[Pt(N₃)₂(OH)₂(NH₃)(2-Br-3-Me-pyridine)]

Trans-[Pt(N₃)₂(NH₃)(2-Br-3-Me-pyridine)] (19.4 mg, 0.041 mmol) wassuspended in H₂O (200 mL) and H₂O₂ (30%, 0.166 mmol, 17 μL) added. Thereaction was stirred in the dark at room temperature for 24 h and thenthe volume reduced to 3 mL. The yellow solution was filtered and thenreduced to dryness. Small amounts of H₂O were added and the solidrecovered by filtration and washed with water, ethanol and diethyl etherthen dried under vacuum.

Yield: 14.4 mg (70.0%)

ESI-MS: [M+Na]³⁰ 525.3 m/z

UV-vis: λ_(max)=288 nm

¹H NMR (90% H₂O/10% D₂O): δ 8.59 (d, H-6, ¹J_(5,6) 6.2 Hz, 1H), 8.09 (d,H-4, ¹J_(4,5) 7.5 Hz, 1H), 7.62 (d, H-5, 1H), 2.59 (s, CH₃, 3H).

Trans,trans,trans-[Pt(N₃)₂(OH)₂(NH₃)(3-pic)] (FM182)Trans-[PtCl₂(NH₃)(3-pic)]

Cisplatin (50.3 mg, 0.168 mmol) was suspended in H₂O (4 mL) and3-picoline (0.504 mmol, 46.9 mg) added. The reaction was stirred at 378K for 1 h or until colourless, then HCl (2.02 mmol, 0.168 mL) added. Thesolution was stirred at 363 K for 12 h then cooled and placed on ice toprecipitate the product, which was collected by filtration. The filtratewas returned to heat at 363 K for a further 12 h and then cooled andfiltered again. The two batches of yellow solid were combined and washedwith water, ethanol and diethyl ether and dried under vacuum.

Yield: 31.1 mg (49.3%)

¹H NMR (d₆-acetone): δ 8.66 (s, H-2, 1H), 8.64 (d, H-6, ¹J_(5,6) 5.9 Hz,1H), 7.78 (d, H-4, ¹J_(4,5) 7.9 Hz, 1H), 7.32 (dd, H-5, 1H), 3.74 (s,NH₃, 3H), 2.37 (s, CH₃, 3H).

Trans-[Pt(N₃)₂(NH₃)(3-pic)]

Trans-[PtCl₂(NH₃)(3-pic)] (9.5 mg, 0.025 mmol) was suspended in H₂O (10mL) and DMF (200 μL). AgNO₃ (2 mol eq, 8.5 mg) was added and thereaction stirred in the dark at 333 K for 24 h. NaN₃ (0.100 mmol, 6.6mg) was added and the solution stirred for 24 f, then all the solventwas removed, H₂O (2 mL) was added and the yellow solid collected byfiltration and washed with water, ethanol and diethyl ether and driedunder vacuum.

Yield: 7.2 mg (73.2%)

¹H NMR (d₆-acetone): δ 8.59 (s, H-2, 1H), 8.57 (d, H-6, ¹J_(5,6) 5.9 Hz,1H), 7.88 (d, H-4, ¹J_(4,5) 7.9 Hz, 1H), 7.46 (dd, H-5, 1H), 3.95 (s,NH₃, 3H), 2.42 (s, CH₃, 3H).

Trans,trans,trans-[Pt(N₃)₂(OH)₂(NH₃)(3-pic)]

Trans-[Pt(N₃)₂(NH₃)(3-pic)] (6.9 mg, 0.018 mmol) was suspended in H₂O(20 mL) and H₂O₂ (30%, 0.071 mmol, 7 μL) added. The reaction was stirredin the dark at room temperature for 24 h and then the volume reduced to3 mL. The yellow solution was filtered to remove any remaining AgN₃ andthen reduced to dryness. Small amounts of H₂O were added and the solidrecovered by filtration and washed with water, ethanol and diethyl etherthen dried under vacuum.

Yield: 6.2 mg (81.4%)

ESI-MS; [M+Na]³⁰ 424.0 m/z

UV-vis: λ_(max)=289 nm (13,575 M⁻¹cm⁻¹)

¹H NMR (90% H₂O/10% D₂O): δ 8.53 (s, H-2, 1H), 8.51 (d, H-6, 1H), 8.07(d, H-4, ¹J_(4,5) 7.9 Hz, 1H), 7.65 (dd, H-5, 1H), 2.50 (s, CH₃, 3H).

Table A sets fort activity data and the methodology of the experimentsset forth above. TABLE A IC₅₀ ^(a) Value (μM) HaCaT A2780 A2780CIS IDStructure Absorption 365 nm Dark 365 nm Dark 365 nm Dark FM137

λmax = 286 nm ε (286 nm) =19,500 M⁻¹cm⁻¹ 154.1 >288.0 99.1 >288.0163.9 >288.0 FM165

λmax = 289 nm ε (289 nm) =18,800 M⁻¹cm⁻¹ 6.1 >244.3 1.9 >244.316.9 >244.3 FM169

λmax = 286 nm ε (286 nm) =19,300 M⁻¹cm⁻¹ 60.3 >276.8 39.9 >276.8128.7 >276.8 FM170

λmax = 285 nm ε (285 nm) =16,500 M⁻¹cm⁻¹ 68.2 >266.5 58.4 >266.590.1 >266.5 FM171

λmax = 293 nm ε (293 nm) =17,900 M⁻¹cm⁻¹ 55.3 >236.2 51.0 >236.259.8 >236.2 FM172

λmax = 288 nm ε (288 nm) =15,200 M⁻¹cm⁻¹ 5.8 >241.0 5.4 187.016.1 >241.0 FM174

λmax = 289 nm ε (288 nm) =14,300 M⁻¹cm⁻¹ 6.5 98.8 FM181

λmax = 288 nm ε (288 nm) Not determined 59.2 98.8 15.8 31.3 38.1 54.4FM182

λmax = 289 nm ε (288 nm) =13,600 M⁻¹cm⁻¹ — — — — — —

Cell Irradiation

2×6 ft Cosmolux RA Plus (Cosmedico), 15500/100 W light sources wereused, each filtered to attenuate UVB/UVC wavelengths. Irradiance wasmeasured with a Waldmann PUMA meter, calibrated to the source using adouble grating Spectroradiometer (Bentham, UK).

Cytotoxicity Assays

Immediately before use, the compounds were dissolved in warm Earle'sBalanced Salt Solution (EBSS), sonicated and vortexed to assistdissolution. For experiments, cells were seeded at densities of 3- or5×10⁴ cells/cm². After overnight incubation, washed cells were incubatedwith test compounds in EBSS for 1 h at 310 K/5% CO₂. Cells were thenirradiated with 5 J cm⁻² glass filtered UVA (1.77 mW cm⁻²: λ_(max) 365nm) for 50 min. Test compounds were removed and cells either preparedimmediately for photogenotoxicity assays, or incubated with completemedium for 24 h before assessing phototoxicity. Control plates weretreated identically to the test plates and sham irradiated.

Phototoxicity was monitored by measuring the uptake of neutral red dyeinto viable cells. Briefly, after irradiation cells were washed and thenincubated with DMEM containing 5% FCS, 1% NEAA and 50 μg ml⁻¹ neutralred dye for 3 h at 310 K/5% CO₂. After this time, cells were rapidlywashed with formaldehyde containing 1% (w/v) CaCl₂, and solubilised in50% EtOH containing 1% acetic acid. Absorbance was read at 540 nmagainst a solubilisation solution as blank. The IC₅₀ value was definedas the concentration of compound that inhibited dye uptake by 50% andwas calculated using non-linear regression (Graphpad Prism). Goodness offit was determined from the R² values of the curves and 95% confidenceintervals.

Photogenotoxicity was assessed using the single cell gel electrophoresisassay (comet assay), immediately after irradiation. The comet assay is asingle cell gel electrophoresis technique used to measure DNA damage inindividual cells. The nuclear DNA of undamaged cells is too large tomigrate in an electrophoretic field under the conditions of the test.However if a clastogenic agent introduces nicks or breaks into themolecule, the free ends, loops, and fragments of DNA can migrate awayfrom the nucleus towards the anode. When stained with a DNA binding dyeand viewed under epifluorescence, the image looks lice a comet. Theseimages are captured by image analysis, and the amount of migrated DNA inthe comet tail quantified. The comet assay can be adapted to distinguishdirect strand-breaks, alkali-labile lesions, oxidised DNA bases,pyrimidine dimers and crosslinks.

Strand breaks were measured using the standard assay protocol, andcross-links by treating washed cells with hydrogen peroxide (H₂O₂, 4°C., 5 min) 30 min after photoactivation and evaluating the extent towhich DNA migration was antagonised. Fifty nuclei per slide wereanalysed by image analysis (Kinetic Imaging, UK). The results wereexpressed as the percentage of DNA that had migrated into the comettail. When necessary, statistical analysis was performed using Dunnett'smultiple comparisons test.

1. A compound defined hereinbelow for use as a medicament for thetreatment of a condition in a patient in which abnormal cells arepresent in the body, which compound is a Pt(IV) complex of the generalformula I:Pt(N₃)₂X¹X²Y¹Y²  (I) wherein X¹ and X² are the same or different andeach one represents a group of the general formula NR¹R²R³ wherein R¹,R² and R³ are the same or different and in each case each one mayrepresent any one of H and optionally substituted alkyl, aryl, aralkyl,acyl, cycloalkyl, heterocyclyl, alkenyl, aralkenyl, alkinyl,cycloalkenyl, or X¹ and X² together represent a group of the generalformula R¹R²NR⁴NR¹R² wherein R¹ and R² have the same meaning ashereinbefore, and R⁴ represents an optionally substituted divalent,saturated or unsaturated, alkyl chain, an optionally substituteddivalent, saturated or unsaturated cycloalkyl or an optionallysubstituted divalent aryl, or R⁴ or two or more of R¹, R², R³ and R⁴ andthe respective N atom(s) to which they are linked, represent anoptionally substituted heterocyclyl having at least one ring containingsaid N atom(s); and Y¹ and Y² are the same or different or, when in acis position, as a further alternative they may together represent adivalent moiety Y³, wherein at least one of Y¹ and Y², or Y³, is alabile ligand in the analogous Pt(II) complex corresponding to generalformula (I) without the azide groups, whilst being resistant, in vivo,to hydrolysis and physiological reducing agents when in the Pt(IV)complex of general formula (I), provided that one or more of R¹, R², R³and R⁴, may further represent a covalently bonded link to at least onefurther complex of formula I so as to form a dimer or oligomer, or to atargeting moiety having affinity for a predetermined tissue or celltype.
 2. A compound according to claim 1 wherein each substituent of asaid substituted group is selected from hydroxyl, alkoxyl, aralkoxyl,carboxy, halogen, trihaloalkyl, and carbonyl.
 3. A compound according toclaim 1 wherein X¹ and X² are in a cis configuration.
 4. A compoundaccording to claim 1 wherein X¹ and X² are in a trans configuration. 5.A compound according to claim 1 wherein Y¹ and Y² are in a transconfiguration.
 6. A compound according to claim 1 wherein the or atleast one said NR¹R²R³ group is selected from pyridyl, quinolyl,isoquinolyl and picolyl.
 7. A compound according to claim 1 wherein saidR¹R²NR⁴NR¹R² group is selected from bipyridyl, phenanthrolyl,1,2-diaminophenyl and 1,2-diaminocyclohexyl.
 8. A compound according toclaim 1 wherein R⁴ represents an optionally substituted divalent,saturated or unsaturated, alkyl chain, said alkyl chain having 2 or 3carbon atoms between the N atoms to which it is linked.
 9. A compoundaccording to claim 1 wherein each of Y¹ and Y² is a labile ligand.
 10. Acompound according to claim 1 wherein one of Y¹ and Y² represents afurther N₃ group.
 11. A compound according to claim 1 wherein at leastone of Y¹ and Y² is a halogen.
 12. A compound according to claim 1wherein at least one of Y¹ and Y² is chlorine.
 13. A compound accordingto claim 1 wherein at least one of Y¹ and Y² represents an OY⁴ groupwherein Y⁴ represents H or a Y⁵CO group wherein Y⁵ represents R, RNH, orRCS, wherein R represents an optionally substituted C1 to C12 alkyl. 14.A compound according to claim 1 wherein Y³ has the general formulaOOC(CY⁶Y⁷)_(n)CY⁸Y⁹O wherein each of Y⁶ and Y⁷ can represent H or asubstituent or Y⁶ and Y⁷ together represent cycloalkyl and n is 0, 1 or2 and each of Y⁸ and Y⁹ can represent H or a substituent or togetherrepresent oxygen.
 15. A compound according to claim 14 wherein Y³ isselected from oxalate or 1,1-dicarboxycyclobutane (CBDCA).
 16. Acompound according to claim 1 wherein said link between said at leasttwo complexes comprises a C4 to C8 alkyl chain.
 17. A compound accordingto claim 1 that is soluble in polar solvents.
 18. A compound accordingto claim 1 which is resistant, in vivo, to glutathione.
 19. A compoundaccording to claim 1 selected from:Cis,trans,cis-[Pt^(IV)(N₃)₂(OH)₂(NH₃)₂],Cis,trans-[Pt^(IV)(en)(N₃)₂(OH)₂] (where en represents ethylenediamine),Trans,cis,cis-[Pt^(IV)(OCOCH₃)₂(N₃)₂(NH₃)₂],[Pt^(IV)(NH₃)₂(CBDCA)trans-(N₃)₂] (where CBDCA represents1,1-dicarboxycyclobutane), and Cis,trans-[Pt^(IV)(cis-dach)(N₃)₂(OH)₂](where dach represents diaminocyclohexane).
 20. A process for generatinga cytotoxic Pt^(II) containing species comprising the steps ofirradiating a compound according to claim 1 with radiation effective forthe reduction of said compound to liberate said N₃ groups.
 21. A processfor synthesising a compound according to claim 1 comprising the steps ofbringing a compound of the formula Pt^(II)(N₃)₂X¹X² into admixture withan oxidising agent under oxidising conditions and oxidising saidPt^(II)(N₃)₂X¹X² to a compound of the formula Pt^(IV)(N₃)₂X¹X²Q¹Q²wherein Q¹ and Q² may be the same as Y¹ and Y² as defined hereinbeforeor different, and, where Q¹ and/or Q² is a group(s) other than Y¹ or Y²,respectively, or together represent a group other than Y³, replacing anysuch Q¹, Q² or Q³ group with said Y¹, Y² or Y³ group(s), wherein saidoxidising agent is H₂O₂ and at least one of Q¹ and Q² is OH.
 22. Aprocess for synthesizing a compound according to claim 1 comprisingreacting a compound of the general formula:PtX¹X²Y¹Y²Z³Z⁴  (IV) wherein X¹, X², Y¹ and Y² have the same meaning asdefined hereinabove, and Z³ and Z⁴ are the same or different and each isa suitably labile leaving group, with an azide salt.
 23. The use of acompound according to claim 1 for the manufacture of a medicament forthe treatment of a condition in a patient in which abnormal cells arepresent in the body, wherein said medicament is in a form in which saidcompound or salt thereof is kept in the dark.
 24. Use according to claim23, wherein said condition is cancer.
 25. Use according to claim 23,wherein said abnormal cells are in the form of a tamour.
 26. A compoundwhich compound is a Pt(IV) complex of the general formula I:Pt(N₃)₂X¹X²Y¹Y²  (I) as defined hereinbefore in claim 1, provided thatsaid compound is not Pt(Py)₂(N₃)₂Cl₂ or Pt(py)₂ClOH.
 27. Apharmaceutical formulation comprising a compound according to claim 1 ora pharmaceutically acceptable salt thereof in a pharmaceuticallyacceptable carrier therefor.
 28. A pharmaceutical formulation accordingto claim 27 which is an oral formulation.
 29. A pharmaceuticalformulation according to claim 27 which is a parenteral formulation. 30.A pharmaceutical formulation product comprising a pharmaceuticalformulation according to claim 27 in a pharmaceutically acceptablecarrier therefor, wherein said product is in a form in which saidcompound or salt thereof is kept in the dark.